Malaria is a major global health burden with annual incidences of approximately 300 million cases and two to three million deaths per year. Ninety percent of malaria cases occur in tropical Africa, with the majority of deaths among children under 5 years old. Development of a vaccine represents an essential goal for an effective control strategy. However, for a vaccine to have a significant impact it would need to be safe, easy to administer, effective in children, and affordable in Africa. A new method of vaccine development involves the engineering of BCG, the widely used tuberculosis vaccine, into a recombinant vaccine vector (rBCG) capable of expressing foreign antigens. Immunization with rBCG expressing viral, bacterial, or parasitic foreign antigens elicits antibody as well as CD4+ and CD8+ T cells responses to the foreign antigens in mice and monkeys. This project will involve the generation of rBCG strains expressing three pre-erythrocytic antigens from mouse malaria, Plasmodium yoelii. Expression of these antigens will be optimized using combinations of promoters and signal sequences. Mice will be vaccinated with the rBCG/malaria strains and challenged with live P. yoelii sporozoites. The immunization studies will test the ability of rBCG/malaria vaccines to stimulate an immune response against the P. yoelii antigens as well as their ability to protect mice against malaria. Mice will also be immunized with a combination vaccine consisting of several rBCG strains expressing different P. yoelii antigens. Finally, based on observations from this work, rBCG strains will be generated expressing the homologous antigens from P. falciparum, which causes over 90 percent of deaths from malaria in humans. These strains will be made available for further testing in mice and humans.